Agonist-dependent internalization of the angiotensin II type one receptor (AT1): role of C-terminus phosphorylation in recruitment of β-arrestins

Kule, Chris E; Karoor, Vijaya; Day, Jonathan N.E.; Thomas, Walter G.; Baker, Kenneth M.; Dinh, D.; Acker, Kathleen Ambruso; Booz, George W.

doi:10.1016/j.regpep.2004.03.001

Cited by 22 publications

(19 citation statements)

References 23 publications

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“…The contribution of intracellular elements to internalization is well described for several GPCRs. In addition to the third intracellular loop these studies revealed a major role of the C terminus in internalization, particularly for the human neuropeptide Y 1 receptor (45), angiotensin II type one receptor (46), human P2Y 1 receptor (47), A 2B adenosine receptor (48), TRHR (49), and the N-formyl peptide receptor (50). However, so far nothing is known about receptor domains involved in hY 2 R internalization.…”

Section: Discussionmentioning

confidence: 99%

Ligand-induced Internalization and Recycling of the Human Neuropeptide Y2 Receptor Is Regulated by Its Carboxyl-terminal Tail

Walther

Nagel

Giménez

et al. 2010

Journal of Biological Chemistry

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Agonist-induced internalization of G protein-coupled receptors plays an important role in signal regulation. The underlying mechanisms of the internalization of the human neuropeptide Y 2 receptor (hY 2 R), as well as its desensitization, endocytosis, and resensitization are mainly unknown. In the present study we have investigated the role of carboxyl-terminal (C-terminal) Ser/Thr residues and acidic amino acids in regulating receptor internalization, arrestin interaction, and recycling by fluorescence microscopy, cell surface enzymelinked immunosorbent assay, and bioluminescence resonance energy transfer in several cell lines. Strikingly, C-terminal truncation mutants revealed two different internalization motifs. Whereas a distal motif 373 DSXTEXT 379 was found to be the primary regulatory internalization sequence acting in concert with arrestin-3, the proximal motif 347 DXXXSEX-SXT 356 promoted ligand-induced internalization in an arrestin-3-independent manner. Moreover, we identified a regulatory sequence located between these internalization motifs ( 357 FKAKKNLEVRKN 368 ), which serves as an inhibitory element. We found that hY 2 R recycling is also governed by structural determinants within the proximal internalization motif. In conclusion, these results indicate that the hY 2 R C terminus is involved in multiple molecular events that regulate internalization, interaction with arrestin-3, and receptor resensitization. Our findings provide novel insights into complex mechanisms of controlled internalization of hY 2 R, which is likely applicable to other GPCRs. G protein-coupled receptors (GPCRs)2 constitute the largest family of cell-surface receptors with ϳ800 known human subtypes. Members of this family share a common architecture of seven membrane-spanning ␣-helices connected by extra-and intracellular loops. GPCRs can be activated by a wide variety of extracellular stimuli and regulate diverse physiological processes (1). Because they are responsible for a multitude of cellular responses and their dysfunction can result in many diseases (2-4), this receptor family represents highly important pharmaceutical targets. More than one-third of the currently available therapeutics act on GPCRs (1). Whereas antagonists mainly prevent receptor interactions with endogenous ligands, agonist drugs might lead to distinct effects in addition to receptor activation, e.g. functional antagonism by receptor removal from the surface (5), direct intracellular cross-signaling (6), and may behave as biased ligands (7). Current information about the complex intracellular network of GPCRs regulation is rather limited. Therefore, it is of great interest to unravel the mechanisms and regulation modalities of receptor internalization and subsequent resensitization processes.The Y 2 R is one of four human neuropeptide Y (NPY) receptor subtypes (hY 1 R, hY 2 R, hY 4 R, and hY 5 R) and belongs to the rhodopsin-like superfamily (class A) of GPCRs. YRs together with their three native ligands, NPY, pancreatic polypeptide (PP), and p...

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Section: Discussionmentioning

confidence: 99%

Ligand-induced Internalization and Recycling of the Human Neuropeptide Y2 Receptor Is Regulated by Its Carboxyl-terminal Tail

Walther

Nagel

Giménez

et al. 2010

Journal of Biological Chemistry

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“…Like other G protein-coupled receptors, AT 1 receptors undergo a process of agonist-induced receptor-mediated endocytosis or internalization (Hein et al, 1997;Hunyady et al, 2000;Gá borik et al, 2001;Holloway et al, 2002;Zhuo et al, 2002;Wyse et al, 2003;Kule et al, 2004). Clathrin-coated pits are the most common pathway for angiotensin II receptor internalization (Bianchi et al, 1986;Thomas, 1999;Gá-borik et al, 2001;Fessart et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Although internalization via clathrin-coated vesicles is the major mechanism for G protein-coupled receptor endocytosis, certain receptors such as the bradykinin, endothelin-1, vasoactive intestinal peptide, muscarinic, and AT 1 receptors have been reported to migrate to and/or be internalized through caveolae upon agonist stimulation and receptor activation (Feron et al, 1997;Haasemann et al, 1998;Ishizaka et al, 1998;Ushio-Fukai et al, 2001;Kule et al, 2004;Houndolo et al, 2005).…”

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confidence: 99%

Methyl-β-cyclodextrin Prevents Angiotensin II-Induced Tachyphylactic Contractile Responses in Rat Aorta

Linder¹,

Thakali²,

Thompson³

et al. 2007

J Pharmacol Exp Ther

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Tachyphylaxis or desensitization is frequently observed following angiotensin II type I (AT 1 ) receptor activation by angiotensin II. One of the possible mechanisms contributing to receptor desensitization involves receptor internalization. In addition to clathrin-coated pits/vesicles, caveolae, small invaginations in the plasma membrane rich in cholesterol, may also be involved in receptor internalization. After activation, AT 1 receptor partially redistributes to lipid-enriched domains. We hypothesize that AT 1 receptor internalization via caveolae contributes to the tachyphylactic response observed to angiotensin II. Endothelium-denuded rat aortic rings were exposed to increasing concentrations of angiotensin II or phenylephrine, generating two cumulative concentration-effect curves (CCEC) with a 90-min interval separating each curve (CCEC-I and CCEC-II). CCEC-II was performed in the presence of either vehicle or methyl-␤-cyclodextrin (CD), a drug that depletes cholesterol from the membrane and disassembles caveolae. CCEC-II to angiotensin II, but not to phenylephrine, was blunted in aortic rings treated with vehicle. In the presence of CD, CCEC-II did not differ significantly from CCEC-I for both agonists. CCEC-I to angiotensin II was abolished when in the presence of the AT 1 receptor antagonist. The presence of AT 1 receptors at the aortic smooth muscle cells' membrane treated with angiotensin II was observed by immunofluorescence only in the presence of CD. In addition, caveolin-1 coimmunoprecipitated with AT 1 receptor after agonist stimulation, and this interaction was inhibited by CD. Our data suggest that caveolae are involved in the tachyphylactic contractile response induced by angiotensin II in rat aorta, and this effect is related to receptor internalization.

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“…Cells were incubated for 5 h at 37°C with 5% CO 2 and then cultured for 24 h in DMEM supplemented with 10% fetal bovine serum, 100 IU/ml penicillin, 100 g/ml streptomycin, and 2 mmol/l L-glutamine. The individual cell lines that stably expressed the recombinant hAT 1/pEGFP-N1 were selected with geneticin (G418 1 mg/ml) and used for all experiments (passages [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19].…”

Section: Methodsmentioning

confidence: 99%

“…␤-Arrestins have also been implicated in receptor endocytosis by a clathrin-dependent pathway (2). Additional internalization mechanisms, such as endocytosis via caveolae or noncoated vesicles, may also occur (10,15,27,31).…”

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confidence: 99%

The effect of angiotensin II on intracellular pH is mediated by AT₁ receptor translocation

Thieme¹,

Eguti²,

Mello-Aires³

et al. 2008

American Journal of Physiology-Cell Physiology

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Agonist-dependent internalization of the angiotensin II type one receptor (AT1): role of C-terminus phosphorylation in recruitment of β-arrestins

Cited by 22 publications

References 23 publications

Ligand-induced Internalization and Recycling of the Human Neuropeptide Y2 Receptor Is Regulated by Its Carboxyl-terminal Tail

Ligand-induced Internalization and Recycling of the Human Neuropeptide Y2 Receptor Is Regulated by Its Carboxyl-terminal Tail

Methyl-β-cyclodextrin Prevents Angiotensin II-Induced Tachyphylactic Contractile Responses in Rat Aorta

The effect of angiotensin II on intracellular pH is mediated by AT₁ receptor translocation

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Agonist-dependent internalization of the angiotensin II type one receptor (AT1): role of C-terminus phosphorylation in recruitment of β-arrestins

Cited by 22 publications

References 23 publications

Ligand-induced Internalization and Recycling of the Human Neuropeptide Y2 Receptor Is Regulated by Its Carboxyl-terminal Tail

Ligand-induced Internalization and Recycling of the Human Neuropeptide Y2 Receptor Is Regulated by Its Carboxyl-terminal Tail

Methyl-β-cyclodextrin Prevents Angiotensin II-Induced Tachyphylactic Contractile Responses in Rat Aorta

The effect of angiotensin II on intracellular pH is mediated by AT1 receptor translocation

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The effect of angiotensin II on intracellular pH is mediated by AT₁ receptor translocation